Introduction

Several vaccines with a different mechanism of action were developed to combat the recent pandemic caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Rare hematologic side effects are emerging with the increased use of these vaccines. Immune thrombocytopenia is the most frequently reported adverse hematologic effect after mRNA- and viral vector vaccines against coronavirus disease 2019 (COVID-19) [1, 2]. Here, we report a case of a severe hyperinflammation syndrome fulfilling the diagnostic criteria for hemophagocytic lymphohistiocytosis (HLH) after immunization with the mRNA COVID-19 vaccine Comirnaty (BNT162b2, Pfizer-BioNTech). We additionally summarize previously identified HLH cases following COVID-19 vaccination and highlight the possible role of a new treatment approach—the additional use of human interleukin 1 receptor antagonist—to improve outcomes of HLH patients.

Methods

A literature search was performed in PubMed for all reported cases of COVID-19 vaccine-associated HLH since database inception until January 18, 2022. The predefined search filter ‘(HLH OR hemophagocytic lymphohistiocytosis OR haemophagocytic lymphohistiocytosis) AND (COVID-19 OR SARS-CoV-2) AND (vaccine OR vaccination)’ yielded 15 results. Reference lists of articles were screened for other suitable studies and authors were contacted to obtain additional data.

Results and discussion

HLH is a life-threatening hyperinflammatory syndrome caused by aberrantly activated macrophages and cytotoxic T cells. HLH can rapidly progress to multiple organ failure and, if untreated, is often fatal [3]. Even with current treatment options, it has a 50% lethality [4]. A 24-year-old, white female with no remarkable medical or travel history developed fever and unspecific fatigue for ten days after the first COVID-19 vaccination with Comirnaty. After a slight improvement of symptoms, she again developed fever, chills, increasing weakness, and nausea from day 13 after vaccination. At the time of presentation at the emergency department on day 16, laboratory testing revealed a reduced total white blood cell count (WBC, 2.4 × 10^9/l), elevated lactate dehydrogenase (LDH, 904 U/l), and slightly elevated aspartate aminotransferase (AST, 72 U/l). The patient was in a reduced general condition with a painful cervical and supraclavicular bilateral lymphadenopathy. Subsequent laboratory testing on day 19 showed a further decrease of the WBC count (1.95 × 10^9/l), an increase of LDH (1184 U/l) and liver function parameters (ASAT 162 U/l, ALAT 121 U/l, GGT 40 U/l), as well as decreased haptoglobin (< 0,1 g/l) (Fig. 1). Serum creatinine levels were normal at all times. Urinalysis was unremarkable. An abdominal ultrasound revealed a splenomegaly (158 × 57 mm), while a computed tomography chest scan confirmed enlarged cervical and supraclavicular lymph nodes with a maximum diameter of 19 × 10 mm. No additional lymphadenopathy or pulmonary infiltrates were detected. Serological and PCR virus tests (EBV, CMV, hepatitis B, C, E, HIV, HSV, Parvo-B19) were negative. The only remarkable value in the serological screening was an increase in Mycoplasma pneumonia IgG (22.3, reference < 9) and IgM (15.9, reference < 9) by enzyme immunoassay, though ten days later, no significant changes in antibody titers were observed. Coombs test, cold agglutinins, hemoglobin electrophoresis and glucose-6-phosphate dehydrogenase activity showed unremarkable results. In immunoblot, antinuclear antibodies (ANA) were positive. ANA differentiation detected antibodies against U1-RNP and PM-Scl. In the absence of other ANA and negative PM-Scl in a control measurement these findings were interpreted as an unspecific reaction. Testing for anti-double-stranded DNA and antineutrophil cytoplasmic autoantibodies (ANCA) was negative. Peripheral blood smears showed few large granular lymphocytes. A bone marrow aspirate and biopsy did not reveal further pathological findings, including no histological evidence for hemophagocytosis.

Fig. 1
figure 1

Changes in body temperature and laboratory parameters over the clinical course. Therapeutic approaches are marked with arrows. ALT alanine transaminase, AP alkaline phosphatase, AST aspartate transaminase, CRP C-reactive protein, GGT gamma glutamyltransferase, IVIG intravenous immunoglobulins, LDH lactate dehydrogenase

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We diagnosed HLH based on the presence of five out of the eight HLH-2004 diagnostic criteria (Fig. 1 and Table 1). The HScore was 259 points (> 99% HLH probability) [5, 6]. During the workup of the patient, 30 g of intravenous immunoglobulins (IVIG) were administered on day 24 after vaccination but did not stop disease progression (Fig. 1). On day 27, dexamethasone 40 mg/d was initiated, but the patient had a steep increase in all HLH-relevant lab parameters including a maximum ferritin of 138.244 µ/l until day 30 and developed an acute liver failure (Fig. 1). In considering alternative treatment options, we reviewed the underlying mechanisms of vaccination-induced HLH. It has been shown that the SARS-CoV-2 spike protein induces IL-1β secretion in macrophages while the pro-inflammatory cytokine IL1-1β has an important role in hyperinflammation syndrome caused by COVID-19 [7]. The mRNA vaccine BNT162b1 encodes the SARS-CoV2 spike protein in full-length [8]. Thus, an IL-1β driven hyperinflammation syndrome after immune-stimulation by mRNA SARS-CoV-2 vaccination is likely a pathomechanism. Based on our understanding, we added the human interleukin 1 receptor antagonist Anakinra to the immunosuppressive treatment on day 29, given that it targets pro-inflammatory cytokine IL1 pathway. The patients’ general condition improved shortly thereafter and fever and abnormal laboratory findings gradually resolved. Dexamethasone was tapered from day 34 onwards, while Anakinra was administered beyond the patient’s discharge on day 41 (Fig. 1).

Table 1 Synopsis of clinical features of patients with hemophagocytic lymphohistiocytosis (HLH) after vaccination against SARS-CoV-2 infection described in literature
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Until now, 16 cases of HLH after COVID-19 vaccination have been described (Table 1) [9,10,11,12,13,14,15,16]. Patients with and without pre-existing conditions and from all age groups (range 20–85 years) were affected. 8/16 cases were female. Seven patients developed HLH after immunization with Comirnaty, six after Vaxzevria (AstraZeneca), two after Spikevax (Moderna) and one after an inactivated SARS-CoV-2 vaccine. Symptoms occurred on average 7.4 days after vaccination (n = 14). 13/15 patients received corticosteroid treatment and 5/15 patients were treated with Anakinra and IVIGs, respectively. Etoposide was used in 2/15 patients. In 8/15 cases, combination therapy was administered. For one patient, treatment was not reported. 3/15 patients died despite appropriate initiation of treatment.

The observed duration between vaccination and onset of symptoms correlates with the upregulation of cytokine signature within days after COVID-19 vaccination [17] and is in line with other studies reporting duration of 10 days between diagnosis of underlying HLH trigger and occurrence of first symptoms [4]. In this case series, etoposide was the agent least frequently administered. The use of etoposide for immunosuppression in HLH according to the HLH-1994 protocol [18] is frequently limited by toxicity in patients with hepatic dysfunction. Comparisons of different HLH treatment strategies in adults with evidence from larger prospective studies are lacking, yet alternative strategies are becoming increasingly available. Anakinra has a good safety profile and a retrospective case series has shown clinical improvement and promising survival rates in combination with IVIGs or/and corticosteroids in patients with reactive HLH [19]. In addition, a favorable response to Anakinra treatment was reported in patients with COVID-19-associated HLH [20]. Anakinra has also been shown to significantly decrease mortality in COVID-19 patients with elevated soluble urokinase plasminogen activator receptor (suPAR) serum levels as a marker of pathogenic inflammation [21]. Based on our and other described reports (Table 1), as well as on a potential influence of pro-inflammatory cytokine IL1-1β [7], we suggest that patients diagnosed with HLH following a SARS-CoV-2 vaccination may benefit from the addition of Anakinra to the immunosuppressive treatment regimen for hyperinflammation syndrome. Moreover, the possibility of a SARS-CoV-2 vaccine-associated HLH should be kept in mind in the clinical routine to initiate early and targeted therapy.